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Thiazolopyrimidine Modulators as Immunosuppressive Agents

a technology of thiazolopyrimidine and modulator, which is applied in the field of thiazolo5, 4dpyrimidine, oxazolo5, 4dpyrimidine, thieno2, 3dpyrimidine and purine derivatives, can solve the problems of severe toxic effects on normal cells, limited number of medicinal chemistry papers that describe the synthesis and biological evaluation of oxazolopyrimidines and thiazolopyrimidines, and achieve significant immuno

Inactive Publication Date: 2015-02-05
KATHOLIEKE UNIV LEUVEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is based on the unexpected discovery that certain combinations of substituents at different positions in the thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine, and purine ring system, not suggested by prior art, meet medical needs and have significant biological properties. These compounds have been found to have immunosuppressive activity, among others. The invention is also related to certain combinations of substituents that show unexpected biological properties, such as inhibiting the growth of tumors or cells. The invention provides new compounds and methods for their use in medicine.

Problems solved by technology

Although purine chemistry is extensively described in literature, the number of medicinal chemistry papers that describe the synthesis and biological evaluation of oxazolopyrimidines and thiazolopyrimidines is limited.
Apparently, the oxazolopyrimidine and thiazolopyrimidine scaffold is not very frequently used in drug discovery programs.
Since these drugs affect mitosis and cell division, they have severe toxic effects on normal cells with high turn-over rate such as bone marrow cells and the gastrointestinal tract lining.
Accordingly, marrow depression and liver damage are common side effects of these antiproliferative drugs.
The common side effects observed with the use of these compounds are frequent infections, abnormal metabolism, hypertension, and diabetes.
However, cyclosporines suffer from a small therapeutic dose window and severe toxic effects including nephrotoxicity, hepatotoxicity, hypertension, hirsutism, cancer, and neurotoxicity.
Introduction of such monoclonal antibodies into a patient, as with many biological materials, induces several side-effects, such as dyspnea.
However, such ideal matches are difficult to achieve.
Further, with the increasing need of donor organs an increasing shortage of transplanted organs currently exists.
Accordingly, xenotransplantation has emerged as an area of intensive study, but faces many hurdles with regard to rejection within the recipient organism.

Method used

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  • Thiazolopyrimidine Modulators as Immunosuppressive Agents
  • Thiazolopyrimidine Modulators as Immunosuppressive Agents
  • Thiazolopyrimidine Modulators as Immunosuppressive Agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of diethyl 2-(4-fluorobenzamido)malonate

[0539]To a solution of diethyl aminomalonate hydrochloride (5.0 g, 23.6 mmol) in pyridine (7.64 ml, 94.5 mmol) and dimethylformamide (60 ml) was added p-fluorobenzoyl chloride (4.19 ml, 35.4 mmol). The reaction mixture was stirred at room temperature for 15 hours. After removing the solvents, the residue was redissolved in dichloromethane, washed with water, brine and dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2 / MeOH 30:1) to yield the title compound as a white solid (4.9 g, 70%).

[0540]1H NMR (300 MHz, DMSO, 25° C.): δ=9.37 (d, J=7.5 Hz, 1H, NH), 7.96-8.01 (m, 2H, PhH), 7.33 (t, J=8.8 Hz, 2H, PhH), 5.30 (d, J=7.5 Hz, 1H, CH), 4.12-4.28 (m, 4H, CH2), 1.22 (t, J=7.1 Hz, 6H, CH3) ppm.

[0541]HRMS: calcd for C14H17FNO5 298.1091, found 298.1092.

example 2

Synthesis of diethyl 2-(2-(4-fluorophenyl)acetamido)malonate

[0542]To a solution of 4-fluorophenylacetic acid (4.5 g, 29.3 mmol) and 1-hydroxybenzotriazole (4.35 g, 32.2 mmol) in dichloromethane (140 ml) was added dicyclohexylcarbodiimide (6.65 g, 32.2 mmol). The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was cooled to 00° C., and then a solution of diethyl aminomalonate hydrochloride (6.2 g, 29.3 mmol) in pyridine (4.5 ml, 29.3 mmol) and DMF (10 ml) was added. The temperature was allowed to rise to ambient temperature. After 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and a 5% NaHCO3 solution. The organic layer was washed with water, brine and dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2 / MeOH 50:1) to yield the title compound as a white solid (8.5 g, 93%).

[0543]1H NMR (300 MHz, CDCl3, 25°...

example 3

Synthesis of dimethyl 2-(3-(4-fluorophenyl)propanamido)malonate

[0545]This compound was synthesized from dimethyl aminomalonate according to the procedure for the preparation of example 2 using 4-fluorophenylpropionic acid. The crude residue was purified by flash chromatography on silica (CH2Cl2 / MeOH 50:1) to yield the title compound as a white solid (53%).

[0546]1H NMR (300 MHz, CDCl3, 25° C.): δ=7.13-7.18 (m, 2H, PhH), 6.96 (t, J=8.7 Hz, 2H, PhH), 6.50 (d, J=6.7 Hz, 1H, NH), 5.19 (d, J=6.7 Hz, 1H, CH), 3.80 (s, 6H, CH3), 2.95 (t, J=7.4 Hz, 2H, CH2), 2.58 (t, J=7.4 Hz, 2H, CH2) ppm.

[0547]HRMS: calcd for C14H17FNO5 298.10908, found 298.10827.

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PUM

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Abstract

The present invention relates to compound of formula I, II, III, or IV, and / or a pharmaceutical acceptable addition salt thereof and / or a stereoisomer thereof and / or a solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, and R12 are as defined in the claim 1. The present invention also relates to a method for their preparation, as well as to pharmaceutical compositions thereof. The present invention further relates to the use of said compounds as biologically active ingredients, more specifically as medicaments for the treatment of disorders and pathologic conditions such as, but not limited to, immune and auto-immune disorders, organ and cells transplant rejections.

Description

FIELD OF THE INVENTION[0001]The present invention relates to a class of novel thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives and a method for their preparation, as well as to pharmaceutical compositions comprising one or more of said thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives and one or more pharmaceutically acceptable excipients. The present invention further relates to the use of said novel thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives as biologically active ingredients, more specifically as medicaments for the treatment of disorders and pathologic conditions such as, but not limited to, immune and auto-immune disorders, organ and cells transplant rejections.BACKGROUND OF THE INVENTION[0002]Thiazolo[5,4-d]pyrimidines and oxazolo[5,4-d]pyrimidines can be considered as structural analogues of purines, in which the imidazo...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D473/32A61K31/5513C07D473/18A61K31/5377A61K31/517A61K45/06
CPCC07D473/32A61K31/517A61K31/5513C07D473/18A61K31/5377A61K45/06A61K31/519A61P29/00A61P35/00A61P37/00A61P37/02A61P37/06A61P43/00C07D513/04
Inventor HERDEWIJN, PIETDE JONGHE, STEVENGAO, LING-JIEJANG, MI-YEONVANDERHOYDONCK, BARTWAER, MARK JOZEF ALBERTLIN, YUANHERMAN, JEAN FERDINANDLOUAT, THIERRY ANDRE MICHEL
Owner KATHOLIEKE UNIV LEUVEN
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